?Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. Enormous progress in basic and translational FXS research has allowed identification of neuronal pathway targets for treatment of the underlying disorder. The most well-studied of these has been pharmacological (using mGluR5 negative allosteric modulators (NAMs)) and genetic reduction of excessive mGluR5 translational pathway signaling to correct abnormal synaptic plasticity, dendritic morphology, cellular signaling, electrophysiological, cognitive, social, behavioral and even growth phenotypes in FXS models. Human early phase trials of mGluR5 NAMs fenobam (Neuropharm), AFQ056 (Novartis) and RO4917523 (Roche) have suggested possible benefit in FXS, but larger phase IIb studies of AFQ056 and RO4917523 failed to meet primary behavioral outcomes in adolescents/adults. These trials may have failed due to lack of measurement of core FXS phenotypes of cognition and learning in a sufficiently young population over a long enough period of time. The proposed project will seek to determine whether the human mGluR5 NAM trials failed because the animal model is not adequate or because the trials were not conducted in a way that benefit could be seen in a neurodevelopmental disorder (NDD). Indeed it may be that the benefits of translational work from preclinical models of NDDs can never be realized via standard drug development pathways. This NeuroNEXT trial seeks to use an innovative exploratory design to change the paradigm for translation of targeted treatments in FXS and determine whether AFQ056 can improve language learning in 100 very young (age 3-6 years) children with FXS during participation in an intensive language learning intervention (LLI), as a surrogate for enhanced neural plasticity. The trial will use a double blind placebo-controlled parallel flexible-dose forced-titration design with a 12 month treatment period during which subjects will be randomized to AFQ056 or placebo with titration to maximum tolerated dose (MTD), followed by treatment with AFQ056/placebo combined with the LLI, then an open-label extension with re-titration to MTD followed by treatment of all participants with LLI and AFQ056, and follow up off AFQ056 at the end of the trial. The study will seek to assess effects of AFQ056 versus placebo on developmental (language, cognitive, adaptive and maladaptive) functioning in young children with FXS receiving the LLI (Aim 1), evaluate safety and tolerability of long-term exposure to AFQ056 in young children with FXS (Aim 2), validate biomarkers that interrogate neural functioning (event-related potentials and eye tracking) and cellular pathway signaling during treatment with AFQ056 and/or LLI and correlate these with developmental outcomes (Aim 3), validate the LLI by evaluating its effects on trajectories of language, cognitive, adaptive, and maladaptive functioning (Aim 4). If the design is successful, this trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other NDDs, and can accelerate the process of bringing needed treatments to these disorders with high unmet need.